ESTROGEN AND PROGESTERONE 



579 



a few days before the expected menstrua- 

 tion (Corner, 1935; Corner and Allen, 1936) . 

 Also, the bleeding that invariably follows 

 the discontinuance of a long treatment with 

 estrogen can be inhibited indefinitely by 

 giving progesterone (Hisaw, 1935; Engle, 

 Smith and Shelesnvak, 1935; Zuckerman, 

 1936b). 



An impression held by many of the ear- 

 lier investigators was that progesterone 

 could not produce its effects on the primate 

 endometrium unless it w^as preceded by the 

 action of estrogen. It is true, of course, that 

 progesterone is a comparatively weak 

 growth promoter and its effects can be dem- 

 onstrated to best advantage on an endo- 

 metrium that has been developed by estro- 

 gen. However, Hisaw, Greep and Fevold 

 (1937) produced a progestational endome- 

 trium in a monkey that had been castrated 

 242 days previously by giving synthetic 

 progesterone. Also, the endometrium of this 

 animal was found capable of forming a 

 decidual plaque upon traumatization. Soon 

 afterwards Hartman and Speert (1941) ob- 

 served menstruation following the with- 

 drawal of progesterone in castrated monkeys 

 that had not been given estrogen and more 

 recently similar results have been reported 

 by Eckstein ( 1950) . At the same time it has 

 l)een found that progesterone will induce 

 menstruation in women suffering from 

 amenorrhea and also that uterine bleeding 

 can l)e jirecipitated l)y similar treatment 

 (hiring tlie follicular j^hase of the cycle 

 (Zondek and Rozin, 1938; Rakoff, 1946). 



These observations have been confirmed 

 and extended by Krohn (1951; 1955) who 

 finds that menstrual bleeding can be in- 

 duced in monkeys wdth secondary amenor- 

 rhea by the injection of 5 daily doses of 

 progesterone. Progesterone (5 mg. daily for 

 5 days) also precipitates uterine bleeding 

 in castrated monkeys at intervals of about 

 8 days provided the treatment is started 

 innnediately a menstrual bleeding has been 

 induced either by removel of the ovaries 

 or withdrawal of estrogen. The most in- 

 teresting aspect of these observations is 

 that the number of short 8-day cycles that 

 can be obtained in this way in a castrated 

 animal seems to be related to the size of the 

 initial dose of estrogen used to induce with- 

 drawal bleeding. This also applies to pro- 



gesterone-withdrawal bleeding, so the ef- 

 fect does not depend upon the particular 

 hormone used to obtain the bleeding. It also 

 is of interest that such conditioning of the 

 endometrium to subsequent responses to the 

 5-day treatments with progesterone may 

 last for several months on a continuous re- 

 gime. It is surprising that such a series of 

 responses cannot be initiated unless the 

 first injection of progesterone is given within 

 6 days following the initial withdrawal 

 bleeding. These observations have much in 

 common with those of Phelps (1947) who 

 also studied the influence of previous treat- 

 ment on experimental menstruation in mon- 

 keys. 



There seems to be a quantitative relation- 

 ship between the dosage of progesterone 

 given in combination with estrogen and the 

 ability of estrogen to prevent bleeding after 

 the injections of progesterone are stopped. It 

 has been mentioned that once a fully 

 developed i^rogestational reaction has been 

 produc(Hl l)y progesterone, it is extremely 

 difficult, if not impossible, to inhibit men- 

 struation by giving estrogen following the 

 withdrawal of progesterone. However, Hi- 

 saw and Greep (1938) found that pro- 

 gestational endometria produced ijy small 

 doses of estrogen plus api^roximately 0.5 

 mg. progesterone daily for 18 to 21 days 

 did not bleed following progesterone with- 

 drawal when continued on 10 to 20 times the 

 original dosage of estrogen. In fact, such 

 endometria were brought back to a condi- 

 tion typical for the action of estrogen and 

 again transformed into a presecretory pro- 

 gestational state without the intervention of 

 bleeding. Similar observations were made 

 previously by Zuckerman (1936a, 1937d). 



These experimental results give grounds 

 for some doubt as to the adequacy of the 

 estrogen-withdrawal theory to account fully 

 for menstruation. Not only can progesterone 

 bring about menstruation without the in- 

 tervention of estrogen but other steroid hor- 

 mones are capable of pi'oducing similar ef- 

 fects. Desoxycorticosterone in large doses 

 can inhibit estrogen-withdrawal bleeding in 

 castrated monkeys (Zuckerman, 1939, 1951 ) 

 and induce phases of uterine bleeding in 

 rapid succession in normal monkeys 

 (Krohn, 1951). So too can testosterone pre- 

 vent estrogen-withdrawal bleeding (Hart- 



